Oral pharmaceutical preparation having androgenic activity

ABSTRACT

The invention relates to an oral pharmaceutical preparation with androgenic activity on the basis of one or more esters of testosterone and/or 5α-dihydrotestosterone, the ester group of which has been derived exclusively from aliphatic carboxylic acids having 9-16 carbon atoms, preferably 10-12 carbon atoms in combination with a non-steroidal lipoid. The preparation may additionally contain a progestational steroid, an oestrogen or a precursor of an A-aromatic steroid.

CROSS-REFERENCE TO RELATED APPLICATION

This is a continuation of application Ser. No. 850,151 filed Nov. 10,1977, which application is a continuation-in-part of Ser. No. 691,103filed Feb. 8, 1976, now U.S. Pat. No. 4,098,802 which is acontinuation-in-part of application Ser. No. 550,397, filed Feb. 18,1975 now abandoned.

The invention relates to an oral pharmaceutical preparation havingandrogenic activity.

It is known to employ testosterone esters as androgenic substances inmedicine, for instance in men with an insufficiency of endogenousandrogens. These compounds are i.a. indicated in a retarded developmentof the external genitals of man, in eunuchoidism, in impotence onendocrine basis, after castration in man, in benign prostatichypertrophy and in geriatry. The androgenic activity of testosteroneester is only revealed in the body after hydrolytic splitting off of theester group. The ester form is used, however, to create a depot-effectand to prevent the quick metabolic decomposition of testosterone.Testosterone esters are therefore employed parenterally as so-calledandrogens with a prolonged activity. On application the esters areinjected while dissolved or suspended in a suitable liquid carrier. Theparenteral form of administration has its inconveniences. Usually apatient cannot give himself an injection and nearly always medical ornursing attendance is needed. Besides that a prolonged parenteraladministration may cause local reactions. An oral administration form isfar to be preferred therefore to the parenteral administration form.

It is known that testosterone shows only very little activity whenadministered orally. Probably it is quickly inactivated by the liver.From experiments it turned out that testosterone esterified with shortchain aliphatic acids (1 to 5 carbon atoms) have also only a slight oralactivity. A similar result was found on oral application of5α-dihydrotestosterone and the short chain esters thereof.

Surprisingly it was found, however, that testosterone esters and5α-dihydrotestosterone esters, derived from aliphatic carboxylic acidswith 9 to 16 carbon atoms, when combined with a non-steroidal lipoidhave a considerably stronger oral androgenic activity than estersderived from short chain aliphatic carboxylic acids. This is all themore surprising since the esters derived from an aliphatic carboxylicacid with more than 16 carbon atoms also turned out to have only aslight oral activity.

The invention therefore relates to an oral pharmaceutical preparationhaving androgenic activity which comprises at least one ester selectedfrom the group consisting of esters of testosterone and5α-dihydrotestosterone, the ester group of which being derivedexclusively from an aliphatic carboxylic acid having 9-16 carbon atoms,and a pharmaceutically acceptable carrier, said carrier comprising anon-steroidal lipoid.

The term "aliphatic carboxylic acid" also includes branched chainaliphatic and cycloaliphatic carboxylic acids.

The preparation according to the invention preferably comprises at leastone testosterone ester and/or 5α-dihydrotestosterone ester derived froman aliphatic carboxylic acid having 10-12 C-atoms which esters turnedout to possess the highest activity.

As examples of aliphatic carboxylic acids with 9-16 carbon atoms, fromwhich the esters are derived, the following can be given: pelargonicacid, capric acid, undecanoic acid, lauric acid, tridecanoic acid,myristic acid, pentadecanoic acid, decenoic acid, undecenoic acid,palmitic acid and the branched chain and cyclic analogues of these acidssuch as α-(and β-)methyl-caprylic acid, α-(and β-)methyl-pelargonicacid, α-(and β-)methyl-capric acid, β,β-dimethyl-pelargonic acid,β-(p-methyl-cyclohexyl)propionic acid, β-(p-ethyl-cyclohexyl)-propionicacid, β-(cycloheptyl)-propionic acid, α-(and β-)methyl-β-cyclohexylpropionic acid, cyclo-dodecyl-carboxylic acid, adamantane-1'-carboxylicacid, adamant-1'-yl-acetic acid andβ-(bicyclo[2,2,2]oct-1'-yl)-propionic acid. The ester is preferablyderived from capric acid, undecanoic acid, lauric acid, tridecanoicacid, myristic acid or the α- or β-methyl-substituted or cyclic isomersof these acids.

Various of the testosterone and 5α-dihydrotestosterone esters indicatedabove are novel compounds. The present invention therefore alsocomprises novel esters with interesting androgenic properties, saidnovel esters having the formula: ##STR1## wherein the dotted lineindicates the optional presence of a double bond, said double bondpreferably being present; n=0 or 1, preferably 0; R₁ =methyl; R₂ =analiphatic group having 5-18 C-atoms, preferably 6-12 C-atoms, whencontaining a cyclo-aliphatic group having 5-12 C-atoms, preferably 5-7C-atoms, or an aliphatic group having 7-18 C-atoms, preferably 8-13C-atoms, when not containing a cyclo-aliphatic group; or R₁ and R₂ formtogether with the C-atom to which they are attached a cyclo-aliphaticgroup having 7-12 C-atoms, said cyclo-aliphatic group optionally beingsubstituted by an aliphatic group having 1-6 C-atoms, with the provisothat the total number of C-atoms in the ester group is in the range of9-16 C-atoms and preferably 10-12 C-atoms.

Typical examples of the novel esters are the 17β-esters derived fromα-methyl-capric acid, β-methyl-capric acid,α-methyl-β-cyclohexyl-propionic acid, β-cyclohexyl-butyric acid, andcyclo-octylcarboxylic acid.

The esters can be prepared according to methods known in the art, forexample by reacting the steroid alcohol with the acid anhydride or withthe acid chloride in the presence of pyridine.

By pharmaceutically acceptable non-steroidal lipoids are meant: thevegetable and animal oils and fats consisting of mono-, di- andtriglycerides of various fatty acids or containing these glycerides asprimary constituent; fatty acid esters of alcohols; higher aliphaticalcohols; saturated or unsaturated fatty acids; the commerciallyavailable synthetic and semi-synthetic mono-, di- and triglyceride oilsand glycerol ethers; certain types of wax and mixtures of two or more ofthe substances mentioned before.

The lipoid substance is preferably liquid at ambient temperature, thatis, at a temperature in the range of about 10° C. to about 30° C. Thetestosterone- or 5α-dihydrotestosterone ester is then dissolved in thelipoid substance and the solution is processed in the preparation orprocessed to a pharmaceutical dosage unit form. Optionally, part of theester is present in the liquid lipoid in suspended form at normaltemperature, whereby the quantities of esters and lipoid substance havepreferably been correlated such that the ester is fully dissolved in thelipoid substance at body-temperature.

Examples of lipoid substances which may be employed in the processaccording to the invention are: arachis oil, castor oil, sesame oil,linseed oil, soya bean oil, sunflower seed oil, olive oil, fish liveroil, ethyl oleate, oleyl oleate, glyceryl trioleate, glyceryl dioleate,glycerylmono-oleate, cetyl alcohol, stearyl alcohol, capric acid,undecenoic acid, undecanoic acid, lauric acid, oleic acid,polyoxyethylene derivatives of glycerides, such as the trade productLabrafil 1944, synthetic glycerides of saturated fatty acids with 8 to10 or 12 carbon atoms, such as the trade products Syndermin CTG andMiglyol 812, bee-wax and mixtures of two or more of these substances.

Preferred lipoid substances are the vegetable oils, such as arachis oil,castor oil, linseed oil and soja oil, further ethyl oleate, oleyloleate, glyceryl mono-oleate, glyceryl trioleate and especially oleicacid.

The combination with non-steroidal lipoid substances has been based onthe one side on the ability of the lipoid substances to increase theoral activity of the androgenic esters and on the other side on thesolubility of the androgenic esters in the lipoid substance. Withrespect to the ability of the lipoid substances to increase the oralactivity of the androgenic esters according to the invention it wasfound that the above preferred lipoid substances roughly possess aboutthe same ability. With regard to the solubility of the androgenic estersin the above preferred lipoid substances it was determined that oleicacid has a high dissolving power, the solubility of for exampletestosterone undecanoate in the temperature range of 15° to 21° C. beingin the range of 175 to 200 mg/ml. For the other preferred lipoidsubstances the solubility of for example testosterone undecanoate atabout 20° C. is in the range of 75 to 150 mg/ml. The solubility is ofimportance, of course, in connection with the desire of limiting thenumber of unit dosage forms that must be taken to cover the necessarydaily intake of androgenic ester.

The present process provides an oral pharmaceutical preparation withandrogenic activity. Contrary to other oral, androgenic pharmaceuticalpreparations, such as those containing methyltestosterone as activesubstance, the preparation according to the invention does not causeinjuries to the liver. The invention also presents the possibility toprepare an orally active, reversible male contraceptive by incorporatinginto the preparation also a substance that suppresses spermatogenesis.Such a substance has an inhibiting effect on the pituitary gland, owingto which the production of gonadotropic hormones is suppressed and/orhas a direct inhibiting effect on the gonads. In this manner a state ofoligospermatism or even azoospermatism is attained. This goes along witha lowering of the endogenous testosterone production owing to which alsothe testosterone level in the plasma is decreased. This may give causefor undesirable side effects, such as impotence and/or loss of libido.It has already been suggested to keep the plasmatestosterone level up tothe mark by combining the oral administration of a substance suppressingspermatogenesis with an intramuscular injection of testosterone estersor a subcutaneous implantation that contains testosterone. In clinicaltrials satisfactory results were obtained with it. For application on alarge scale this dosing methodology has considerable drawbacks as amatter of course.

As substance suppressing spermatogenesis an orally active progestativesteroid can be employed. Thus by incorporating into the preparationaccording to the invention also an orally active progestative steroid apreparation is obtained with which by way of oral administration thespermatogenesis in man is decreased to an infertile level and theconcurrent decrease of the plasma testosterone level is simultaneouslycompensated.

Examples of orally active progestative steroids are the(19-nor-)testosterone derivatives: 17α-ethynyl-Δ⁴ -oestrene-17β-ol(lynestrenol), 17α-ethynyl-Δ⁵ -oestrene-17β-ol (cingestol),6α-methyl-17α-ethynyl-17β-hydroxy-Δ⁴ -androsten-3-one (dimethisteron),17α-ethynyl-17β-hydroxy-Δ⁴ -oestrene-3-one (norethisteron) and the17β-acetate of it, 17α-ethynyl-17β-hydroxy-Δ⁵(10) -oestren-3-one(nor-ethynodrel), 17α-ethynyl-17β-hydroxy-18-methyl-Δ⁴ -oestren-3-one(nor-gestrel), 17α-ethynyl-Δ⁴ -oestren-3β,17β-diol 3,17β-diacetate(ethynodiol diacetate), 17α-ethynyl-17β-hydroxy-Δ⁴,9,11-oestratrien-3-one and the corresponding 18-methyl-compound,17α-ethynyl-17β-hydroxy-Δ⁴ -oestreno-(2,3-d)-isoxazole (danazol),7α-methylethynodioldiacetate, 11β-chloro-lynestrenol,11β-chloro-norethisteron, 7α-methyl-norgestrel and11β-methyl-norethisterone, and the (19-nor-)-progesteron-derivatives:6-chloro-17α-acetoxy-Δ⁴,6 -pregnadiene-3,20-dione (chlormadinonacetate), 6-methyl-17α-acetoxy-Δ⁴,6 -pregnadiene-3,20-dione (megestrolacetate), 6-methyl-16-methylene-17α-acetoxy-Δ⁴,6 -pregnadiene-3,20-dione(melengestrolacetate), 9β,10α-Δ⁴,6 -pregnadiene-3,20-dione(dydrogesteron), 6-chloro-9β,10α-Δ¹,4,6 -pregnatriene-3,20-dione,17α-hydroxy-Δ⁴ -pregnene-3,20-dione 17α-caproate and the corresponding19-nor-compound, 6α- methyl-17α-acetoxy-Δ⁴ -pregnene-3,20-dion(medroxyprogesterone acetate) and 17α-acetoxy-Δ⁴,6-19-norpregnadiene-3,20-dione.

Preferably a 3-desoxo-steroid of the oestrane series is employed asprogestative steroid, such as lynestrenol, cingestol,11β-chloro-lynestrenol and other 11β-substituted lynestrenols and18-methyl-lynestrenols.

The invention also offers the possibility of preparing an oralpharmaceutical preparation having beside androgenic propertiesoestrogenic properties by incorporating into the preparation accordingto the invention an orally active oestrogen, such as17α-ethinyl-oestradiol, mestranol or quinestrenol, or a precursor of anA-aromatic steroid such as 19-hydroxy-testosterone.

There is a want in medicine for such preparation having balancedandrogenic/oestrogenic properties, in a number of indications,especially for climacteric complaints in women and men, for promoting afeeling of general well-being in post-climacteric women and men, fortreating frigidity in women and impotence in men caused by a disturbanceof the hormonal equilibrium in the body.

Thus, another embodiment of the invention is an oral pharmaceuticalpreparation comprising an ester of testosterone and/or5α-dihydro-testosterone, the ester group of which has been derivedexclusively from an aliphatic carboxylic acid having 9-16 carbon atoms,an oestrogen or a precursor of an A-aromatic steroid and a lipoidsubstance as defined before.

The preparation according to the invention can be administered orally invarious dosage forms, for instance in the form of tablets, capsules,granules, pills, boluses, coated tablets, powders, granulates ormicro-capsules. Besides the androgenic ester(s) and the oily componentand/or the progestative substance, the dosage forms may contain one ormore of the usual excipients, for instance benzyl alcohol for enhancingthe solubility of the active substance in the oil component, water,thickeners such as gelatin or agar-agar, polyethylene glycols, lactose,starch or magnesium stearate. If necessary also adjuvants may bepresent, such as preservatives, emulsifying agents, stabilisers, wettingagents, flavours, dyes, fillers, binding agents and/or coating agents.

The capsules may be soft or hard gelatin capsules, in which the activeprinciple and the lipoid are present in granular or finely dividedintimate admixture, in the form of a suspension in a liquid or in theform of an oily solution, if necessary even partly in suspension andpartly in solution.

The combination of (5α-dihydro-)testosterone-17β-ester and lipoid, whenliquid or semi-liquid, may also be processed to solid oral formulationssuch as pills, or tablets. For that purpose the oily solution of thesteroid ester is, for example, absorbed on calcium phosphate, lactose orcellulose derivatives and then processed to tablets or pills in theusual way. Combinations of the steroid esters of the invention withlipoids, such as glycerylmono-oleate or capric acid, which are solid orsemi-solid at room temperature, may be granulated and processed tocoated pills or tablets.

The most suitable oral administration form for this liquid form of thepreparation according to the invention is the soft gelatine capsule ormicrocapsule. In accordance with a method usual in the technique, theoily solution containing the active components and optionally otheringredients is encapsulated to soft gelatine capsules or microcapsuleswith the desired dimensions and containing the desired amount(s) ofactive substances. The microcapsules can also be processed to tablets orpills according to well-known pharmaceutical formulation methods.

The androgenic ester(s) concentration in the preparation according tothe invention can vary within considerable limits, on the understandingthat the amount of androgenic ester(s) by weight does not exceed theamount of lipoid substance by weight or in other words the androgenicester(s) concentration in the preparation is 50% by weight or less andis usually in the range of 1-40% by weight.

As indicated above, the amount of lipoid by weight in the preparationaccording to the invention is equal to or higher than the amount ofandrogenic ester by weight. Depending on the other constituents presentin the preparation (excipients, capsule-shell, coating) the amount oflipoid substance per dosage unit will vary from 25 to 95% by weight andis usually in the range of 50-80% by weight. The amount of androgenicester(s) per dosage unit, for example a capsule or a tablet, may alsovary within wide limits, for example from 0.5 to 400 mg, and ispreferably between 1 and 200 mg.

For practical reasons the amount of lipoid substance in the preparationis usually within the range of about 2 to 25 times the amount ofandrogenic ester (or esters) on a weight basis.

The quantity of progestative substance, used in the male contraceptive,depends on the potency of the substance in question and may vary between0.1 and 1000 mg and is preferably between 0.2 and 100 mg per unit dosageform. The amount of oestrogen or precursor of an A-aromatic steroid, ifused in the preparation of the invention, depends on the potency of thesubstance in question and on the desired balance of androgen/oestrogenproperties in the preparation and may vary between 0.002 and 2 mg forthe oestrogen and between 0.1 and 500 mg for a precursor of anA-aromatic steroid, per unit dosage form.

The special biological properties of the novel preparations can bedemonstrated for example by experiments in castrated rats (Hershbergertest), wherein the increase in weight of the seminal vesicles and theventral prostate is determined after having orally dosed the activesubstance for seven days once or twice a day.

In this way it turned out in such an experiment that with a daily oraldosage of 2×2 mg in arachis oil, the androgenic activity of testosteronedecanoate, testosterone undecanoate and testosterone dodecanoate was 2to 3 times greater than that of testosterone, testosterone propionate,testosterone oenanthate, testosterone arachidate and testosteronebehenate. Similar results were also found with the5α-dihydro-testosterone esters.

In another experiment testosterone undecanoate (TU) was tested invarious lipoids and without a lipoid (Table A).

                  Table A                                                         ______________________________________                                        2 × 2 mg/day/orally                                                                    wt % (control = 100)                                             TU in        seminal vesicles                                                                           ventral prostate                                  ______________________________________                                        sun-flower oil 540          680                                               Syndermin GTC  550          690                                               olive oil      610          680                                               tablet (crystalline form)                                                                    270          460                                               ______________________________________                                    

Further tests according to Hershberger with 17-esters of testosteroneand 5α-dihydrotestosterone derived from aliphatic carboxylic acidshaving X carbon atoms, after a daily oral administration of 2×1 mg inarachis oil for seven days, gave the results of Table B.

                  Table B                                                         ______________________________________                                                         wt % seminal                                                                              wt % ventral                                                      vesicles    prostate                                         X                (control = 100)                                                                           (control = 100)                                  ______________________________________                                        Testosterone esters                                                            5               150         370                                               7               190         360                                               9               290         510                                              10               380         670                                              11               420         620                                              12               260         460                                              13               205         420                                              16               200         430                                              18               175         390                                              5α-Dihydrotestosterone esters                                            0               226         270                                               3               212         316                                               5               166         277                                               8               225         290                                              10               322         442                                              11               420         412                                              12               346         365                                              16               262         308                                              ______________________________________                                    

The table of Table B indicate that the oral pharmaceutical preparationsaccording to the invention have very strong androgenic properties. Whenthe weight percentage of testosterone and 5α-dihydrotestosterone in theesters (testosterone and 5α-dihydrotestosterone being the activeconstituent in the esters thereof) is taken into account then theactivities are even higher and grow relatively higher as X increases.

In another comparative test (Hershberger test) testosterone (T),testosterone decanoate (T 10) and testosterone dodecanoate (T 12) weretested in crystalline form (A) and in arachis oil (B) at a daily oraldose of 2×2 mg for seven days (Table C).

                  Table C                                                         ______________________________________                                                Oral dosage                                                                              wt % sem. ves.                                                                            wt % ventr. prost.                             Compound                                                                              form       (control = 100)                                                                           (control = 100)                                ______________________________________                                        T       A          180         350                                            T       B          230         370                                            T 10    A          320         390                                            T 10    B          560         670                                            T 12    A          270         290                                            T 12    B          510         610                                            ______________________________________                                    

The data of Table C clearly demonstrate the positive influence of thelipoid in the oral pharmaceutical preparation according to theinvention, whereas for testosterone itself there is hardly anyinfluence.

A comparative test including branched chain esters gave the resultsillustrated in Table D (Hershberger test).

                  Table D                                                         ______________________________________                                        Testosterone ester                                                                          wt %                                                            (orally in    seminal vesicles                                                                           wt % ventral prost.                                arachis oil)  (control = 100)                                                                            (control = 100)                                    ______________________________________                                        decanoate     310          590                                                α-methyl-β-cyclohexyl-                                                           770          730                                                propionate                                                                    β-cyclohexyl-butyrate                                                                  680          750                                                undecanoate   340          500                                                α-methyl-decanoate                                                                    790          700                                                β-methyl-decanoate                                                                     620          710                                                ______________________________________                                    

The data of Table D illustrate the remarkable increase in activity byα-methyl and β-methyl substitution of the ester group.

In clinical trials with preparations according to the invention, whereina daily dose of testosterone ester in the range from 50 to 200 mg wasadministered, a considerable increase of the plasmatestosterone levelwas found both in men with a normal plasmatestosterone level and in menwith a lower level resulting from a decreased production of endogenoustestosterone.

A clinical trial with a daily oral dose of 80 mg testosteroneundecanoate in 0.5 ml oleic acid (two soft gelatine capsules of 40 mgester in 0.24 ml oleic acid) for three months in a hypogonadal man gavea remarkable improvement in his libido and his sexual, physical andmental activities. The plasmatestosterone level was markedly increasedfrom 50 ng/100 ml to 200 ng/100 ml.

The clinical trials indicate that the use of the oral preparationsaccording to the invention is an effective form of androgen substitutiontherapy in hypogonadal male patients.

The invention is illustrated with the following examples:

EXAMPLE I Soft gelatin capsules

A sterile solution of testosterone undecanoate in arachis oil was made,containing 41.67 g per liter. Under aseptic conditions this solution wasencapsulated, according to the usual soft gel encapsulating technique.In this manner soft gelatine capsules were obtained with a content of0.24 ml so that the content of active substance per capsule was 10 mg.The wall of the capsule (113 mg) consisted of 77 mg of gelatine, 17.5 mgof glycerol, 15.5 mg of sorbitol, 0.5 mg of sodium-para-hydroxy-benzoicacid ethyl/propyl ester, 0.6 mg of TiO₂ and 1.9 mg of Cochineal red A(dye).

In the same manner testosterone caprate, testosterone α-methylcaprate,5α-dihydro-testosterone laurate and testosterone myristate wereprocessed into soft gelatine capsules, containing 10 mg of activesubstance in arachis oil (0.24 ml).

EXAMPLE II Soft gelatine capsules

A sterile solution was made of testosterone undecanoate in glyceryltrioleate, containing 80.64 g per liter. In the manner as indicated inexample I, this solution was encapsulated. Soft gelatine capsules wereobtained with a content of 0.31 ml, containing 25 mg of testosteroneundecanoate. In a similar manner testosterone pelargonate wasencapsulated into soft gelatine capsules containing 0.31 ml of asolution of 35 mg of the ester in ethyl oleate, and a mixture of equalportions of testosterone caprate and testosterone laurate wasencapsulated into soft gelatine capsules, containing 0.31 ml of asolution of 20 mg of the ester-mixture in glyceryl trioleate.

                  Example III                                                     ______________________________________                                        Tablets                                                                       ______________________________________                                        Testosterone undecanoate                                                                              25 mg                                                 Undecanoic acid         50 mg                                                 Lactose                 145 mg                                                Potato starch           28 mg                                                 Magnesium stearate      2 mg                                                                          250 mg                                                ______________________________________                                    

While gently heating, the testosterone undecanoate was dissolved in theundecanoic acid, whereafter this solution was absorbed homogeneously inthe lactose. After mixing with potato starch and a little water, thethus obtained granulate was dried. The dry granulate was mixed withmagnesium stearate as lubricant and tabletted in the usual manner.

In a similar manner tablets of the following composition weremanufactured:

    ______________________________________                                        5α-Dihydrotestosterone laurate                                                                   25 mg                                                Lynestrenol              5 mg                                                 Methyl cellulose         15 mg                                                Glyceryl mono-oleate     88 mg                                                Lactose                  115 mg                                               Magnesium stearate       2 mg                                                                          250 mg                                               ______________________________________                                    

EXAMPLE IV

    ______________________________________                                        Hard gelatin capsules                                                         ______________________________________                                        Testosterone undecanoate                                                                              100 mg                                                Stearyl alcohol         375 mg                                                Norethisteron           25 mg                                                                         500 mg                                                ______________________________________                                    

Testosterone undecanoate is dissolved at 60° C. in stearyl alcohol.After cooling the solid mixture is triturated and thoroughly mixed withnorethisteron. With the mixture thus obtained, hard gelatine capsulesare dispensed.

EXAMPLE V

A sterile solution of testosterone undecanoate in oleic acid was made,containing 166.67 g per liter. In the manner as indicated in example I,this solution was encapsulated to soft gelatine capsules with a contentof 0.18 ml, thus containing 30 mg of the testosterone ester per capsule.

In a similar manner testosterone α-methyl-β-cyclohexylpropionate inoleic acid was encapsulated to soft gelatine capsules with a content of0.18 ml, containing 20 mg of the ester per capsule.

EXAMPLE VI

Testosterone undecanoate was dissolved in undecanoic acid at 30° C. Thesolution contained 277.78 g ester per liter. This solution wasencapsulated to soft gelatine capsules with a content of 0.18 ml, thuscontaining 50 mg of ester per capsule.

EXAMPLE VII Preparation of novel esters

To a solution of 2 g testosterone in a mixture of 8 ml pyridine and 8 mlacetone, cooled to -10° C., was added dropwise in a nitrogen atmospherea solution of 4 ml α-methyl-decanoyl-chloride in 12 ml acetone. Themixture was stirred for 16 hours at 0° C., whereafter 4 ml pyridine and8 ml water were added to the mixture. The mixture was stirred for 1 hourat 0° C. and 2 hours at 45° C. and then poured out in 200 ml ice-water.Extraction with diethylether neutralisation of the extracts, evaporationof the diethylether and chromatography of the residue on silicagel withtoluene/ethylacetate 8/2 gave 3.0 g testosterone α-methyl-caprate in theform of an oil with [α]_(D) ²⁰ =+77.0° (in methylenechloride) andε_(mol) 16.800 (λ_(max) 240 mμ).

In a similar manner the following 17β-esters were prepared:

testosterone β-methyl-caprate

testosterone α-methyl-β-cyclohexylpropionate

testosterone β-cyclohexyl-butyrate

testosterone β-cycloheptyl-propionate

testosterone cyclododecylcarboxylate

5α-dihydrotestosterone α-methylcaprate.

We claim:
 1. Testosterone β-methyl-caprate.
 2. 5α-Dihydrotestosteroneα-methyl-caprate.
 3. Testosterone β-cycloheptyl-propionate.
 4. A steriodester having the formula: ##STR2## wherein: (a) the dotted lineindicates the optional presence of a double bond;(b) n=0 or 1; (c) R₁ ismethyl; and (d) R₂ is selected from the group consisting of an aliphatichydrocarbon of 8 carbons and cyclohexyl; or R₁ and R₂ form together withthe carbon atom to which they are attached a cycloaliphatic group having8 carbon atoms, with the proviso that the total number of carbon atomsin the ester group is in the range of 9-16 carbon atoms.
 5. Testosteroneβ-cyclohexyl-butyrate.